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Drosophila gain-of-function mutant RTK torso triggers ectopic Dpp and STAT signaling
1Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, New York 14642, USA.
Abstract:
Overactivation of receptor tyrosine kinases (RTKs) has been linked to tumorigenesis. To understand how a hyperactivated RTK functions differently from wild-type RTK, we conducted a genome-wide systematic survey for genes that are required for signaling by a gain-of-function mutant Drosophila RTK Torso (Tor). We screened chromosomal deficiencies for suppression of a gain-of-function mutation tor (tor(GOF)), which led to the identification of 26 genomic regions that, when in half dosage, suppressed the defects caused by tor(GOF). Testing of candidate genes in these regions revealed many genes known to be involved in Tor signaling (such as those encoding the Ras-MAPK cassette, adaptor and structural molecules of RTK signaling, and downstream target genes of Tor), confirming the specificity of this genetic screen. Importantly, this screen also identified components of the TGFbeta (Dpp) and JAK/STAT pathways as being required for Tor(GOF) signaling. Specifically, we found that reducing the dosage of thickveins (tkv), Mothers against dpp (Mad), or STAT92E (aka marelle), respectively, suppressed tor(GOF) phenotypes. Furthermore, we demonstrate that in tor(GOF) embryos, dpp is ectopically expressed and thus may contribute to the patterning defects. These results demonstrate an essential requirement of noncanonical signaling pathways for a persistently activated RTK to cause pathological defects in an organism.
Insights
Hyperactivated receptor tyrosine kinases (RTKs) drive cancer. This study identified new genes, including those in TGFbeta and JAK/STAT pathways, required for RTK signaling, revealing noncanonical pathway roles in tumorigenesis.
Area of Science:
- Molecular Biology
- Genetics
- Developmental Biology
Background:
- Overactivation of receptor tyrosine kinases (RTKs) is implicated in cancer development.
- Understanding the signaling mechanisms of hyperactivated RTKs is crucial for cancer research.
Purpose of the Study:
- To conduct a genome-wide screen for genes essential for signaling by a hyperactivated Drosophila RTK, Torso (Tor).
- To identify novel components and pathways involved in oncogenic RTK signaling.
Main Methods:
- A genetic screen using chromosomal deficiencies to suppress a gain-of-function mutation in the Drosophila Torso (tor(GOF)).
- Validation of candidate genes involved in known RTK pathways and identification of novel pathway interactions.
Main Results:
- Identified 26 genomic regions suppressing tor(GOF) phenotypes, including known RTK signaling genes.
- Discovered that components of the TGFbeta (Dpp) and JAK/STAT pathways are required for tor(GOF) signaling.
- Demonstrated ectopic expression of Dpp in tor(GOF) embryos, suggesting its role in developmental defects.
Conclusions:
- Persistently activated RTKs require noncanonical signaling pathways, such as TGFbeta and JAK/STAT, to induce pathological defects.
- This study reveals unexpected links between RTK signaling and other major developmental pathways in the context of oncogenesis.